This invention relates to treatment for the inhibition or reduction of colon tumorigenesis in a mammal by the administration of a pharmaceutical compound.
Evidence from epidemiological studies suggests an association of consumption of cruciferous vegetables and a reduced risk of colon cancer (31). Although a number of compounds in these vegetables may collectively cause the beneficial effects, there has been a need to identify the exact role of each compound that contributes to the protective effects. Ample data from laboratory animal studies have shown that isothiocyanates (ITCs), one of the major constituents of cruciferous vegetables, are promising chemopreventive agents against cancers at various sites, including lung, esophagus, liver, mammary, and bladder (3, 32, 33). These laboratory results support a potential role of dietary ITCs in reducing risk of certain human cancers. However, it is well known to those of skill in the art that chemopreventive agents affect different tissues differently.
Previously, for example, it has been reported that while phenylhexyl ITC, a synthetic homologue of PEITC, is a potent inhibitor of lung tumorigenesis, it enhanced colon and esophagus tumorigenesis in rats, possibly due to its tissue cytotoxicity at the dose level studied (29, 30). These results illustrate the importance of considering tissue specificity and of choosing the appropriate dose range for specific tissues in chemoprevention studies.
A recent case-control study reported that broccoli consumption is linked to a lowered risk of colon cancer, and the protective effect is especially evident in individuals with a glutathione transferase (GST) M1 null genotype (1). Because GSTs facilitate the conjugation of ITCs resulting in their excretion as the N-acetylcysteine NAC) conjugates via the mercapturic acid pathway, it has been suggested that the ITC compounds in broccoli may play a role in the protection of human colon cancer (2). Sulforaphane (SFN) is the predominant ITC found in broccoli which has been studied for its chemopreventive potential due to its activity in the induction of phase II enzymes involved in carcinogen detoxification and elimination (3). However, so far no animal data is available regarding the effects of SFN on colon tumorigenesis. Several laboratory animal studies have shown that phenethyl ITC (PEITC), a principal constituent in watercress, is a potent chemopreventive agent for cancers of the breast, lung, and esophagus (4, 5, 6). However, there is insufficient data for PEITC on colon cancer.
Considering the natural abundance of SFN and PEITC in broccoli and watercress, respectively, and their potential as chemopreventive agents, it is surprising that little is known about the effects of these agents on colon tumorigenesis. A lower homologue of PEITC, benzyl ITC (BITC) has been shown to inhibit colon tumor incidence in AOM treated rats during the initiation phase, but not during the post-initiation phase (34). Another short-term study, however, has reported that both PEITC and BITC given in the diet at similar dose levels were inactive towards ACF formation, in fact, BITC was found to slightly induce ACF formation (10). By contrast, the present inventors have now demonstrated for the first time that both PEITC and SFN inhibit colonic ACF, independent of whether they are administered before or after carcinogen exposure.
There is provided in accordance with one embodiment of the invention a method for inhibiting tumor development in a mammal. The method comprises administering to the mammal a pharmacologically effective amount of an isothiocyanate selected from the group consisting of sulforaphane and phenethyl isothiocyanate. The sulforaphane may be isolated from broccoli and the phenethyl isothiocyanate may be isolated from watercress. The isothiocyanate is preferably administered to the mammal as a purified compound, either alone or in a composition with a pharmacologically acceptable carrier, excipient or diluent or with a beverage or foodstuff.
In a preferred embodiment of the invention, the mammal is a human and the isothiocyanate is administered to the human as a dietary supplement. In a preferred treatment regimen, the isothiocyanate is administered to the human in a dosage of between about 0.5 and 12 mg/kg body weight per day.
In another embodiment of the invention there is provided a method for treating colon tumor formation in a mammal in need of such treatment. The method comprises administering to the mammal a pharmacologically effective amount of an isothiocyanate selected from the group consisting of sulforaphane and phenethyl isothiocyanate.
The above and other features and advantages of the invention will be found in the detailed description which follows below.